There are over one million workers in the United States exposed to welding fumes as part of their job duties. The process of welding produces concentrated particulate fumes and gases including manganese. Concerns have arisen about exposure to manganese and the subsequent development of Parkinsonism and cognitive impairment. Positron emission tomography studies demonstrate asymptomatic welders have reduced 6-[18F]fluoro-L-DOPA uptake implying pre-clinical dysfunction of nigrostriatal pathways. Unfortunately, large scale use of this modality would be challenging and costly. In this set of experiments the investigators wil investigate resting state-functional connectivity MRI (rs-fcMRI) as a functional marker of manganese neurotoxicity in exposed welders. The specific aims will test the following hypotheses: 1) welding with manganese exposure will cause abnormal functional connections on rs-fcMRI between basal ganglia and cognitive control networks; 2) welders with clinical manganese neurotoxicity will have greater abnormalities in functional connectivity within basal ganglia and executive control networks than exposed but asymptomatic welders; 3) rs-fcMRI can identify functional connectivity abnormalities that are potential antecedent biomarkers for the subsequent development of clinical neurotoxicity including cognitive impairment and parkinsonism. These studies will have implications for our understanding of mechanisms of manganese neurotoxicity and its relationship to Parkinsonism and cognitive dysfunction. Furthermore, study results and the techniques employed will be useful for future development of functional biomarkers of both neurotoxins and neurodegenerative processes. The candidate is an Assistant Professor of Neurology at Washington University in St. Louis, Missouri. Her short-term goal is to enhance her functional neuroimaging skills so that she can transition from mentored to independent patient-oriented research employing functional imaging to investigate the neurotoxicity of manganese exposure. Once the mechanistic relationships between manganese exposure and symptomatic neurotoxicity are described, the longer-term goal is to develop functional biomarkers of neurotoxicity. Results from these neuroimaging studies would have implications for understanding the complex mechanisms of neurotoxicity from occupational exposures such as manganese and improve worker safety by better defining exposure thresholds. Development of functional markers including pre-clinical markers will be essential for future intervention/prevention trials and testing of dose-response relationships. The multidisciplinary team of world- class mentors and the extensive intellectual and physical resources available at Washington University will optimize my training experience, the likelihood for successful transition to independent research, and chances for a long successful career in neurotoxicity and functional connectivity research. Public Health Relevance: Welding is a common occupation performed by over 1 million workers in the United States and exposes workers to potentially toxic manganese fumes. Unfortunately, there are no cost effective biomarkers of manganese neurotoxicity and the pathophysiology of this condition is poorly understood. This study will employ advanced neuroimaging techniques to investigate functional networks in the brain and decipher the pathophysiology of Mn induced neurotoxicity. Knowledge gained from these studies should lead to biomarkers for intervention/prevention trials and testing of dose-response relationships resulting in improved workplace safety for thousands of welders.